Background: The BRAF V600E mutation (BRAF-m) occurs in approximately 7% of patients with metastatic CRC (mCRC). Encorafenib (enco) in combination with cetuximab (cetux) was approved in April 2020 as the first targeted regimen for the treatment of adult patients with mCRC with BRAF-m. The purpose of this study is to analyze the post-approval real-world persistence and adherence to treatment with enco in combination with cetux or with panitumumab (pani), an alternative EGFR, in mCRC, based on a claims database in the US. Methods: This was a retrospective cohort study in the IQVIA PharMetrics Plus claims database (2013-2022). Adults ≥18 years old with ≥1 claim for enco (first claim for enco on/after 4/1/2020) with concurrent EGFR (cetux or pani), ≥2 ICD-9/10 codes for malignancy of the colon or rectum ≥30 days apart in the 1 year before index date, and ≥1 day of pharmacy and medical continuous enrollment during the index date were included. Patients were excluded if they had a record of melanoma or non-small cell lung cancer during the year before index date, were enrolled in a clinical trial any time after the CRC diagnosis date or did not have a treatment regimen starting on or after CRC diagnosis date. Index date was the date of first treatment of enco + EGFR during the identification period (4/1/2020-3/31/2022). Patient demographics and disease characteristics were assessed at baseline, adherence (measured as at least 80% of days covered) and persistence (measured as time to discontinuation by Kaplan-Meier method) were estimated during the follow-up period. Results: 125 patients were included. Median (Q1 [1^st quartile], Q3 [3^rd quartile]) age at index was 58 (49, 63) years and 52.0% were female. Metastases were present in 3 or more sites in 60.8% of the patients, in 1 or 2 sites in 37.6%. The 2011 Modified Quan Charlson Comorbidity Index was 0 for 44.8% of the patients, 1-2 for 39.2%, and 3 or more for 16.0%. Most patients received cetux as their EGFR combined with enco (77.6%). Adherence to enco + EGFR was high (85.6%); enco + cetux vs. enco + pani: 89.7% vs. 74.1%. Median (Q1, Q3) proportion of time on cetux while on enco was 87.9% (77.9%, 94.3%) and median (Q1, Q3) proportion of time on pani while on enco was 79.9% (70.0%, 90.0%). Median (95% confidence interval) time to enco regimen discontinuation during follow-up was 6.2 (4.9–8.8) months. Conclusions: This up-to-date study provides current real-world evidence on the use of enco + EGFR in mCRC BRAF-m patients in the US. The results show high levels of adherence to the treatment, suggesting high tolerability to encorafenib, and persistence consistent with clinical trial evidence.